Immunotherapy is based on the premise that there are intrinsic differences in the protein composition of tumor cells that allow the immune system to recognize tumor cells as ?foreign? and eradicate them. There is increasing evidence that tumors respond to immunotherapy [1], particularly in scenarios of minimal disease [2- 4]. Because immunotherapy is effective in treating small amounts of disease, it seems ?obvious? that if one could reduce tumor size with surgery/chemotherapy, the addition of immunotherapy would eliminate the minimal amount of residual disease and lead to a cure (i.e. the concept of adjuvant immunotherapy). Unfortunately, dozens of clinical trials using immunotherapy (usually vaccines) after surgery for a variety of cancers have been conducted and virtually all have failed [5-7]. As a graduate student, I obtained data suggesting that debulking surgery fails to eliminate immunosuppressive networks consisting of cellular and soluble factors at the (i) resection site, (ii) draining lymph nodes and (iii) blood [2]. The overarching hypothesis of this proposal is that disruption of post-operative immunosuppressive networks is necessary to maximize efficacy of immunotherapy. Using Malignant Pleural Mesothelioma (MPM) as a model, our proposed research aims to (1) determine the potential efficacy and mechanisms of a series of clinically available agents hypothesized to decrease immunosuppressive effects and (2) analyze combinations of immunotherapy, surgery, and chemotherapy in order to identify the optimal regimen for future clinical trials. MPM is an excellent choice to study this approach as the disease remains essentially incurable despite multi-modal approaches (including surgery, chemotherapy, radiation) [8] and our group has greater than 15 years of experience in human immunotherapy clinical trials for MPM [9-14]. The research will also serve as a training platform for the applicant towards competency in tumor immunology, mammalian cell techniques, and murine experiments, as well as provide the applicant with mentoring towards the goal of becoming an independent investigator in translational tumor immunology. This work will set the stage for the next generation of clinical trials which combines multi-modal immunotherapy with surgical resection for patients with MPM. These findings will also be applicable to other malignancies that are treated with surgery, chemotherapy and radiation.